The acquired immunodeficiency syndrome (AIDS) and infection with the human immunodeficiency virus type 1 (HIV-1) constitute a worldwide public health problem. Venkatesan, Science, 241, 1481-1485 (1988). HIV is an RNA retrovirus that was originally designated human T-lymphotropic virus (HTLV-III), lymphadenopathy-associated virus (LAV), or AIDS associated retrovirus (ARV). Fauci, Science, 239, 617 (1988). HIV is commonly referred to as HIV-1 to differentiate it from HIV-2, a clinical syndrome indistinguishable from HIV-induced AIDS which has been isolated from West African patients. The virus shares many features with other members of the nontransforming and cytopathic lentivirus family of retroviruses.
The critical basis for the immunopathogenesis of HIV infection is the depletion of the CD4+ helper/inducer subset of T-cells, resulting in profound immunosuppression. See Dahlgleish et al, Nature, 312, 763 (1984); Fauci, Clin. Res., 32, 491 (1985), Ho et al. N. Engl. J. Med., 317, 278 (1987). HIV has a selective tropism for CD4.sup.+ T-cells and macrophages which is mediated by interaction of its envelope (env) protein gp120with an essential component of the cell surface receptor for HIV-1, the CD4 antigen. Lasky et al. Science, 233, 209 (1986). After HIV binds to the first domain of the CD4 molecule via the external envelope glycoprotein gp 120, the virus is internalized and uncoated. Fauci, Science, 239, 617 (1988). Once uncoated, the viral genomic RNA is transcribed to DNA by the enzyme reverse transcriptase. The proviral DNA is then integrated into the host chromosomal DNA. After integration of the provirus, the infection may assume a latent phase or the proviral DNA may transcribe viral genomic RNA and messenger RNA. Protein synthesis, processing, and virus assembly occur with budding of the mature virion from the cell surface.
At present, AIDS is incurable and treatment modalities that reduce HIV-1 replication in vivo by using reverse transcriptase inhibitors such as zidovudine/ZDV (formerly termed azidothymidine/AZT) and dideoxyinosine (ddI) cause substantial side effects. Yarchoan et al., Blood, 78, 859 (1991). Although ZDV delays the disease progression in HIV-1 seropositive asymptomatic individuals and has improved the survival of patients with AIDS and AIDS-related complex (ARC), the therapeutic response is frequently transient. Volberding et al., N Engl J Med, 322, 941 (1990); Fischl et al., Ann Intern Med, 112, 727 (1990); Fischl et al., N Engl J Med, 317, 185 (1987). Variants of HIV-1 that are resistant to ZDV emerge to thwart the success of continued therapy. Erice et al., Clinical Infectious Diseases, 18, 149 (1994). Recent data indicate that resistance among HIV-1 isolates also emerges during dideoxyinosine (ddI) therapy. St Clair et al., Science, 253, 1557 (1991). These characteristics emphasize the resilience of HIV-1 and the need for more powerful strategies against this virus.
It has been reported that HIV-1 replication in normal CD4.sup.+ T cells can be inhibited in vitro by pokeweed antiviral protein (PAP). Zarling et al., Nature 347: 92-95, (1990). Notably, targeting PAP to CD4+ T cells in vitro by conjugating it with monoclonal antibodies reactive with CD4.sup.+ T-cells increased its potency &gt;1,000-fold in inhibition of HIV-1 replication (Zarling et al., Nature 347: 92-95, 1990; U.S. patent application Ser. No. 07/979,470). Subsequent studies using clinical isolates of AZT-sensitive and AZT-resistant HIV-1 demonstrated that G17.2(anti-CD4)-PAP immunoconjugate exhibits potent anti-HIV activity against all isolates at nanomolar concentrations (Erice et al., Antimicrobial Agents and Chemotherapy 37: 835-838, 1993). Despite these very encouraging in vitro data, the clinical development of PAP immunoconjugates for treatment of HIV-1 infected individuals has been hampered by the poor in vivo stability of anti-T cell directed immunoconjugates. Consequently, therapeutic concentrations of T-cell directed PAP immunoconjugates were impossible to attain in vivo. For example, G17.2(anti-CD4)-PAP immunoconjugate (disclosed in U.S. patent application Ser. No. 07/979,470) showed no detectable anti-HIV-1 activity in SCID mouse models of human AIDS. Thus, a need exists for an anti-T cell PAP immunoconjugate with improved stability that is efficacious in vivo.